Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Yian Lin; Adam X. Maihofer; Emma Stapp; Megan Ritchey; Ney Alliey-Rodriguez; Amit Anand; Yokesh Balaraman; Wade H. Berrettini; Holli Bertram; Abesh Bhattacharjee; Cynthia V. Calkin; Carla Conroy; William Coryell; Nicole D'Arcangelo; Anna DeModena; Joanna M. Biernacka; Carrie Fisher; Nicole Frazier; Mark Frye; Keming Gao; Julie Garnham; Elliot Gershon; Kara Glazer; Fernando S. Goes; Toyomi Goto; Elizabeth Karberg; Gloria Harrington; Petter Jakobsen; Masoud Kamali; Marisa Kelly; Susan G. Leckband; Falk W. Lohoff; Andrea Stautland; Michael J. McCarthy; Melvin G. McInnis; Francis Mondimore; Gunnar Morken; John I. Nurnberger; Ketil J. Oedegaard; Vigdis Elin Giever Syrstad; Kelly Ryan; Martha Schinagle; Helle Schoeyen; Ole A. Andreassen; Marth Shaw; Paul D. Shilling; Claire Slaney; Bruce Tarwater; Joseph R. Calabrese; Martin Alda; Caroline M. Nievergelt; Peter P. Zandi; John R. Kelsoe

doi:10.1111/bdi.13078

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Yian Lin, Adam X. Maihofer, Emma Stapp, Megan Ritchey, Ney Alliey-Rodriguez, Amit Anand, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Abesh Bhattacharjee, Cynthia V. Calkin, Carla Conroy, William Coryell, Nicole D'Arcangelo, Anna DeModena, Joanna M. Biernacka, Carrie Fisher, Nicole Frazier, Mark Frye, Keming GaoJulie Garnham, Elliot Gershon, Kara Glazer, Fernando S. Goes, Toyomi Goto, Elizabeth Karberg, Gloria Harrington, Petter Jakobsen, Masoud Kamali, Marisa Kelly, Susan G. Leckband, Falk W. Lohoff, Andrea Stautland, Michael J. McCarthy, Melvin G. McInnis, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Ketil J. Oedegaard, Vigdis Elin Giever Syrstad, Kelly Ryan, Martha Schinagle, Helle Schoeyen, Ole A. Andreassen, Marth Shaw, Paul D. Shilling, Claire Slaney, Bruce Tarwater, Joseph R. Calabrese, Martin Alda, Caroline M. Nievergelt, Peter P. Zandi, John R. Kelsoe

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Original language	English (US)
Pages (from-to)	821-831
Number of pages	11
Journal	Bipolar disorders
Volume	23
Issue number	8
DOIs	https://doi.org/10.1111/bdi.13078
State	Published - Dec 2021

Keywords

bipolar disorder
clinical predictor
lithium
treatment response

ASJC Scopus subject areas

Psychiatry and Mental health
Biological Psychiatry

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10.1111/bdi.13078

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Lin, Y., Maihofer, A. X., Stapp, E., Ritchey, M., Alliey-Rodriguez, N., Anand, A., Balaraman, Y., Berrettini, W. H., Bertram, H., Bhattacharjee, A., Calkin, C. V., Conroy, C., Coryell, W., D'Arcangelo, N., DeModena, A., Biernacka, J. M., Fisher, C., Frazier, N., Frye, M., ... Kelsoe, J. R. (2021). Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study. Bipolar disorders, 23(8), 821-831. https://doi.org/10.1111/bdi.13078

Lin, Y, Maihofer, AX, Stapp, E, Ritchey, M, Alliey-Rodriguez, N, Anand, A, Balaraman, Y, Berrettini, WH, Bertram, H, Bhattacharjee, A, Calkin, CV, Conroy, C, Coryell, W, D'Arcangelo, N, DeModena, A, Biernacka, JM, Fisher, C, Frazier, N, Frye, M, Gao, K, Garnham, J, Gershon, E, Glazer, K, Goes, FS, Goto, T, Karberg, E, Harrington, G, Jakobsen, P, Kamali, M, Kelly, M, Leckband, SG, Lohoff, FW, Stautland, A, McCarthy, MJ, McInnis, MG, Mondimore, F, Morken, G, Nurnberger, JI, Oedegaard, KJ, Syrstad, VEG, Ryan, K, Schinagle, M, Schoeyen, H, Andreassen, OA, Shaw, M, Shilling, PD, Slaney, C, Tarwater, B, Calabrese, JR, Alda, M, Nievergelt, CM, Zandi, PP & Kelsoe, JR 2021, 'Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study', Bipolar disorders, vol. 23, no. 8, pp. 821-831. https://doi.org/10.1111/bdi.13078

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title = "Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study",

abstract = "Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.",

keywords = "bipolar disorder, clinical predictor, lithium, treatment response",

author = "Yian Lin and Maihofer, {Adam X.} and Emma Stapp and Megan Ritchey and Ney Alliey-Rodriguez and Amit Anand and Yokesh Balaraman and Berrettini, {Wade H.} and Holli Bertram and Abesh Bhattacharjee and Calkin, {Cynthia V.} and Carla Conroy and William Coryell and Nicole D'Arcangelo and Anna DeModena and Biernacka, {Joanna M.} and Carrie Fisher and Nicole Frazier and Mark Frye and Keming Gao and Julie Garnham and Elliot Gershon and Kara Glazer and Goes, {Fernando S.} and Toyomi Goto and Elizabeth Karberg and Gloria Harrington and Petter Jakobsen and Masoud Kamali and Marisa Kelly and Leckband, {Susan G.} and Lohoff, {Falk W.} and Andrea Stautland and McCarthy, {Michael J.} and McInnis, {Melvin G.} and Francis Mondimore and Gunnar Morken and Nurnberger, {John I.} and Oedegaard, {Ketil J.} and Syrstad, {Vigdis Elin Giever} and Kelly Ryan and Martha Schinagle and Helle Schoeyen and Andreassen, {Ole A.} and Marth Shaw and Shilling, {Paul D.} and Claire Slaney and Bruce Tarwater and Calabrese, {Joseph R.} and Martin Alda and Nievergelt, {Caroline M.} and Zandi, {Peter P.} and Kelsoe, {John R.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.",

year = "2021",

month = dec,

doi = "10.1111/bdi.13078",

language = "English (US)",

volume = "23",

pages = "821--831",

journal = "Bipolar disorders",

issn = "1398-5647",

publisher = "Blackwell Munksgaard",

number = "8",

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TY - JOUR

T1 - Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

AU - Lin, Yian

AU - Maihofer, Adam X.

AU - Stapp, Emma

AU - Ritchey, Megan

AU - Alliey-Rodriguez, Ney

AU - Anand, Amit

AU - Balaraman, Yokesh

AU - Berrettini, Wade H.

AU - Bertram, Holli

AU - Bhattacharjee, Abesh

AU - Calkin, Cynthia V.

AU - Conroy, Carla

AU - Coryell, William

AU - D'Arcangelo, Nicole

AU - DeModena, Anna

AU - Biernacka, Joanna M.

AU - Fisher, Carrie

AU - Frazier, Nicole

AU - Frye, Mark

AU - Gao, Keming

AU - Garnham, Julie

AU - Gershon, Elliot

AU - Glazer, Kara

AU - Goes, Fernando S.

AU - Goto, Toyomi

AU - Karberg, Elizabeth

AU - Harrington, Gloria

AU - Jakobsen, Petter

AU - Kamali, Masoud

AU - Kelly, Marisa

AU - Leckband, Susan G.

AU - Lohoff, Falk W.

AU - Stautland, Andrea

AU - McCarthy, Michael J.

AU - McInnis, Melvin G.

AU - Mondimore, Francis

AU - Morken, Gunnar

AU - Nurnberger, John I.

AU - Oedegaard, Ketil J.

AU - Syrstad, Vigdis Elin Giever

AU - Ryan, Kelly

AU - Schinagle, Martha

AU - Schoeyen, Helle

AU - Andreassen, Ole A.

AU - Shaw, Marth

AU - Shilling, Paul D.

AU - Slaney, Claire

AU - Tarwater, Bruce

AU - Calabrese, Joseph R.

AU - Alda, Martin

AU - Nievergelt, Caroline M.

AU - Zandi, Peter P.

AU - Kelsoe, John R.

PY - 2021/12

Y1 - 2021/12

N2 - Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

AB - Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

KW - bipolar disorder

KW - clinical predictor

KW - lithium

KW - treatment response

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U2 - 10.1111/bdi.13078

DO - 10.1111/bdi.13078

M3 - Article

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SN - 1398-5647

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EP - 831

JO - Bipolar disorders

JF - Bipolar disorders

IS - 8

ER -

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

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